A new DES-mediated synthesis of Henna-based benzopyranophenazines and benzoxanthenetriones

MTPPBr/THFTCA-DES was prepared as a new deep eutectic solvent (DES) from a mixture (molar ratio 7:3) of methyltriphenyl-phosphonium bromide (MTPPBr) and tetrahydrofuran-2,3,4,5-tetra-carboxylic acid (THFTCA), and characterized with various spectroscopic techniques, densitometer, and eutectic point. Then, it was used as a new and powerful catalyst for the synthesis of two sets of biologically important compounds, namely the Henna-based benzopyranophenazines and benzoxan-thenetriones. Solvent-free conditions, short reaction time, high efficiency, and easy recycling and separation of the DES catalyst are among the most important features of the presented method. Also, there is a nice consistency between the proposed structure of the DES compound, the integration values of the 1H NMR peaks, and the ratio of MTPPBr to THFTCA obtained from the eutectic point phase diagram. In addition, the reduction of peak splitting patterns in DES compared to the two primary materials can be good evidence of the formation of hydrogen bonds between the two components.

Then, the catalytic ability of the new obtained DES was studied in the synthesis of the two sets of the following biological active compounds: A) the ten new [3(a-j)] and the twelve known [3(k-v)] Henna-based benzopyranophenazines from the reaction of 2-hydroxynaphthalene-1,4-dione, 1,2-phenylenediamine, aldehyde and malononitrile, and B) the twelve known [4(a-l)] benzoxanthenes-triones from the reaction of 2-hydroxynaphtha-lene-1,4-dione, aldehyde, and dimedone in a cheap, simple, and non-toxic method with high yields and short reaction times in solvent-free conditions (Scheme 2).

Experimental Materials and methods
Comprehensive information about the starting materials suppliers, and the used scientific equipments for characterization of the DES and all prepared compounds are found in Supporting Information.

General procedure for preparation of a new DES compound
The mixture (molar ratio 7:3) of MTPPBr (7 mmol) and THFTCA (3 mmol) were stirred at 140 °C until a homogeneous transparent liquid obtained.Then, H 2 O (20 mL) and EtOAc (20 mL) were added and DES extracted from the aqueous layer, dried at room temperature and stored for further reactions 17 .After completion of the reaction (TLC, n-hexane/ethyl acetate 8:2), the mixture was washed with ethanol and filtered to separate the catalyst (the reaction mixture is insoluble in ethanol and the DES catalyst is soluble).Ethanol was removed from the filtrate and the DES catalyst stored for further reactions.
A solid precipitate was washed with ethanol and characterized with comparison of their FT-IR, 1 H-NMR, 13 C-NMR, Mass spectra, and melting points with authentic samples.
After completion of the reaction (TLC, n-hexane/ethyl acetate 8:2), the mixture was diluted with water (20 mL) and ethyl acetate (20 mL) and shaked (the reaction mixture is insoluble in water and the DES catalyst is soluble).The aqueous layer was separated by, water removed and DES stored for further reactions.
A solid precipitate was washed with water and characterized with a comparison of their FT-IR, 1 H-NMR, and melting points with authentic samples.

Ethical approval
Hereby, as a corresponding author, I (Davood Habibi) am responsible for ensuring that all the descriptions in this manuscript are accurate and agreed upon by all authors in such a manner as to meet the standard of the Journal (Research on Chemical Intermediates.

Results and discussion
DESs, which are an important class of organic compounds, have expanded greatly in recent years as environmentally friendly compounds and acts as both a solvent and a catalyst.The catalytic performance of these compounds is based on the ability to create hydrogen bonds between itself and starting materials.www.nature.com/scientificreports/

Characterization of DES
The new DES catalyst was characterized by different techniques such the FT-IR, eutectic point, 1 H NMR, TGA/ DTA, and densitometer.

Characterization by FT-IR
Figure 1 shows the FT-IR spectra of MTPPBr (a), THFTCA (b), MTPPBr/THFTCA-DES (c), and the recovered DES catalyst (d).In spectrum (a), the peaks at about 2900-3100 cm −1 are related to the aromatic and aliphatic hydrogens, and the peaks at about 750 and 1480 cm −1 are related to the C-P bonds, respectively.In spectrum (b), the peaks at 3600 and 1735 cm −1 are related to the O-H and C = O of the -COOH group, respectively.In spectrum (c), the above-mentioned peaks can be seen in both (a) and (b) spectra, which confirm the structure of the DES catalyst.Also, similarity of the IR spectrum of the used DES with the fresh one, confirms the structure of the recovered DES.

Characterization by eutectic point
To check the best ratio and the chemical composition of the MTPPBr to THFTCA, the eutectic point experiment was performed.So, ten different portions (100-0%) of MTPPBr with a melting point about 230 °C were added to the ten different portions (0-100%) of THFTCA with a melting point about 205 °C and the obtained melting points were recorded each time.Figure 2 shows that the best-obtained ratio of MTPPBr to THFTCA is about 7 to 3 (almost 2:1) with the melting point about 90 °C.

Characterization by 1 H NMR
Figure 3 shows the 1 H NMR spectrum of MTPPBr/THFTCA-DES.The peaks at 3.12-3.18(d, 6H), 7.85 (m, 30H), 8.61 (s, 4H), and 13.51 ppm (s, 4H) are related to the CH 3 hydrogens, the phenyl rings, the CH of THFTCA, and the CH of acid (THFTCA), respectively.The decrease in the splitting patterns of the peaks in DES, compared to the raw materials can be very nice evidence of hydrogen bond formation between the two components.The formed hydrogen bonds have caused a gap between the phenyl groups in THFTCA and the methyl groups in MTPPBr, so the long-range coupling is no longer possible.
Also, there is a very nice consistency between the proposed structure for the DES compound (Scheme 1) and the integration values of the 1 H NMR peaks (Fig. 3).The ratio of the peak integration values of the Hs of the CH 3 groups, the Hs of the phenyl groups, the acidic Hs of the THF tetra-acid, and the Hs of the THF cycle   Figure 4 shows two weight losses in the 365 and 511 °C regions.The first one is probably related to the breakdown of the hydrogen bonds of acidic compound, and the second one is related to the breakdown of the ionic bonds.Also, the DTG curve shows two small breaks below 200 °C, which can be related to the removal of small amount of water and organic solvent.

Characterization by densitometer
Since most DESs are denser than water, a certain amount of DES mixed with a certain volume of water, then by using the formula (P = P w /1−m w /m d ), the density of the new prepared DES was calculated (P = P w /1−m w /m d = 0 .99618/1-0.0472/0.1811= 1.34733 g/mL), which is about 1.34733 g/mL.

Optimization of the reaction conditions for the synthesis of 3d
The effect of different parameters on the reaction rate was investigated by the use of the model reaction conditions (reaction of 2-hydroxynaphthalene-1,4-dione, 1,2-phenylenediamine, malononitrile, and benz-aldehyde).So, reactions were performed in various solvents and solvent-free conditions by different amounts of DES at different temperatures.

Synthesis of diverse 3(a-v) compounds (Supp Info)
Based on the results obtained from the optimal conditions (synthesis of 3d), the condensation reactions of 2-hydroxynaphthalene-1,4-dione, 1,2-phenylenediamines, malononitrile, and aldehydes were carried out for the synthesis of 3(a-v) in short reaction times and good yields to show the capability of the DES catalyst (Table 2).

A proposed mechanism for the synthesis of 3(a-v) compounds
The possible mechanism for the synthesis of 3(a-v) compounds is shown in Scheme 3. First, the intermediate (I) is formed from the nucleophilic attacks of the two -NH 2 groups of benzene-1,2-diamine to the two DES activated carbonyl groups of 2-hydroxynaphthalene-1,4-dione.Also, intermediate (III) is formed from the nucleophilic attack of the imine form of malononitrile to the DES activated carbonyl group of an aldehyde with the subsequent deletion of water from intermediate (II).Then, a possible intermediate (IV) is formed via the addition of (I) to (III).Finally, tautomerization of IV and its successive internal cyclization will produce the final product (V).www.nature.com/scientificreports/

Reusability of DES
After completion of the model reaction (compound 3n) at the optimum point, the reaction mixture was diluted with water and chloroform and shaked.Then, the aqueous layer containing the DES catalyst was separated from the organic layer by simple liquid-liquid extraction, dried, and reused in consecutive runs without any significant loss of the catalytic activity (95, 90, 88, and 86%, respectively), confirming the stability of the DES catalyst (Fig. 5).

Comparison of the catalyst activities
Table 3 shows the higher efficiency and better performance of the DES catalyst, compared with the other reported catalysts in the synthesis of 3(a-v) compounds.

Optimization of the reaction conditions for the synthesis of 4f
The effect of different parameters on the reaction rate was investigated by the use of the model reaction conditions (reaction of 2-hydroxynaphthalene-1,4-dione, dimedone and benzaldehyde).So, reactions were performed in various solvents and solvent-free conditions by different amounts of DES at different temperatures.
The best result was found to be the 1:1:1 mol ratio of 2-hydroxynaphthalene-1,4-dione, dimedone, and benzaldehyde with 1.5 mmol of the DES catalyst at 80 °C in solvent-free conditions with high yield in short reaction time (Table 4).

Synthesis of diverse 4(a-l) compounds (Supp Info)
Based on the results obtained from the optimal conditions (synthesis of 4f), the condensation reaction 2-hydroxynaphthalene-1,4-dione, dimedone, and various aldehydes were carried out to synthesize a wide range of the 4(a-l) compounds.The products were synthesized in a short reaction time and good yields to show the catalytic capability of the MTPPBr/THFTCA-DES compound (Table 5).

A proposed mechanism for the synthesis of 4(a-l) compounds
The possible mechanism for the synthesis of 4(a-l) is shown in Scheme 4. The DES catalyst activates the carbonyl group of the aldehyde for the nucleophilic attack of dimedone (or 1,3-dicarbonyl compound) on it to form (I) with the subsequent release of water to form (II).The reaction is continued by the Michael's addition of 2-hydroxy-1,4-naphthoquinones to (II) to form (III).The intermediate (IV) is formed by the keto-enol tautomerization of (III), which its intermolecular cyclization will form (V). The final product (VI) is formed by removing water from (V).

Reusability of DES
After completion of the model reaction (compound 4f) at the optimum point, the reaction was stopped and the mixture was diluted with water and chloroform and shaked vigorously.The DES catalyst inside the aqueous layer was separated from the organic layer by simple liquid-liquid extraction and dried to remove water.Then, it was reused in consecutive runs which showed a small decrease in the catalytic activity (90, 87, 85, and 80%, respectively), confirming the stability of the DES catalyst (Fig. 6).

Comparison of the DES catalyst with other catalysts
Table 6 shows the higher efficiency and better performance of the DES catalyst, compared with the other reported catalysts in the synthesis of 4(a-l) compounds.

Conclusion
In summary, DESs have recently gained attention as a cost-effective and environmentally friendly alternative to organic synthesis.They can be easily synthesized by mixing and heating the components without the need for purification, and making them energy-efficient.DES not only act as a solvent but also as a recyclable and reusable organocatalyst, therefore, it can play a dual role in organic transformations.The use of DES catalysts has many advantages such as reasonable yields of desired products, short reaction times, low costs of starting materials for catalyst preparation, mild reaction media, and versatile work-up procedures.Using DES with appropriate features, we can develop test protocols that are environmentally friendly, cost effective, and maximally efficient.
In conclusion, a new DES was prepared from a 7:3 mixture of MTPPBr and THFTCA and its structure confirmed by different techniques.The ratio of the peak integration values of Hs of the CH 3 groups, Hs of the phenyl groups, Hs of the tetra acid, and Hs of the THF cycle is 6:30:4:4 indicating the presence of the two CH 3 groups, the six phenyl groups, the four acidic hydrogens, and the one THF cycle.Incidentally, the decrease in splitting patterns of the peaks in DES, compared to the two starting materials can be very nice evidence of hydrogen bond formation between the two components.
Then, the new DES compound was used as an efficient, capable, and recyclable catalyst based on its ability to form hydrogen bonds in the synthesis of Henna-based benzopyranophenazines and benzo-xanthenetriones with short reaction times, the high yields.In addition, the new DES compound not only plays the role of the catalyst, but also plays the role of a solvent to provide a mild environmental condition for starting materials to perform the expected reactions.

Scheme 3 .Figure 5 .
Scheme 3. Proposed mechanism for the synthesis of 3(a-v) by the DES catalyst.

Scheme 4 .Figure 6 .
Scheme 4. Proposed mechanism for the synthesis of 4(a-l) by the new DES catalyst.

Table 1 .
Optimization of the reaction conditions in the synthesis of 3(a-v) compounds.

Table 3 .
Comparison of the new DES catalyst with the other reported catalysts in the synthesis of 3(a-v).

Table 4 .
Optimization of the reaction conditions for the synthesis of 4

Table 6 .
Comparison of the new DES catalyst with the other reported catalysts in the synthesis of 4(a-l).